1. Field of the Invention
The invention relates to a process for the alkylation of dihydroxythiophenedicarboxylic esters or their alkali metal or alkaline earth metal salts in the presence of organic onium salts.
2. Brief Description of the Prior Art
3,4-Dialkoxythiophenes and 3,4-alkylenedioxythiophenes are starting compounds for the preparation of electrically conductive polymers which may be transparent in thin layers and have recently been finding a wide range of uses. The polymers are used, for example, as electrodes, sensors, for producing capacitors or electroluminescent displays and other electro-optic components, for producing photovoltaic devices, as electrochromic layers, as auxiliaries for the production of metal coatings, as thin films for dissipating static charges, in gel electrolytes or in ion-exchange membranes. The properties of these polymers can be varied within wide limits by means of the length and the substitution pattern of the alkoxy or alkylene group. The polymers are generally prepared from the corresponding monomers by chemical or electrochemical methods. A particularly important 3,4-alkylenedioxythiophene is 3,4-ethylenedioxythiophene.
3,4-Dialkoxythiophenes and 3,4-alkylenedioxythiophenes are frequently prepared in a multistage synthesis from the corresponding 3,4-dialkoxythiophene-2,5-dicarboxylic acids and 3,4-alkylenedioxythiophene-2,5-dicarboxylic acids by decarboxylation. These acids are in turn prepared from the corresponding esters. 3,4-Dialkoxythiophene-2,5-dicarboxylic esters and 3,4-alkylenedioxythiophene-2,5-dicarboxylic esters can be prepared by alkylation of 3,4-dihydroxythiophene-2,5-dicarboxylic esters. While 3,4-dihydroxythiophene-2,5-dicarboxylic esters and their alkali metal and alkaline earth metal salts have for a long time been able to be obtained conveniently in good yield (cf. for example, O. Hinsberg, Ber. Dt. Chem. Ges. 43, 1910, 901-906 and 45, 1912, 2413-2418), their alkylation is in many cases difficult and able to be carried out only in moderate yields.
Merz et al., J. Prakt. Chem. 338, 1996, 672-674, describe the alkylation of 3,4-dihydroxythiophene-2,5-dicarboxylic esters which is carried out using dimethyl sulphate in toluene in the presence of the cation solvator [18]crown-6, giving a yield of free dicarboxylic acid of 73% of theory. However, a disadvantage of this process is the long reaction time of 48 hours. Furthermore, the starting material is used in the form of its dipotassium salt which has to be prepared separately from the diol. The alkylation using 1,2-dichloroethane as alkylating agent, which is said to lead to 3,4-ethylenedioxythiophene-2,5-dicarboxylic ester which is preferably used as starting material for preparing 3,4-ethylenedioxythiophene, was not able to be reproduced in the laboratory under the conditions stated.
M. Coffey et al., Synthetic Communications 26 (11), 1996, 2205-2212, describe the alkylation of 3,4-dihydroxythiophene-2,5-dicarboxylic esters in the form of the free diol by means of 1,2-dibromoethane in the presence of potassium carbonate at 150xc2x0 C. in dimethylformamide. A disadvantage is the low yield of 52% of theory. In addition, the preparation of the free diol from the alkali metal salt initially obtained is an additional process step which has an adverse effect on the economics of the synthesis. A variant of this method in which the reaction temperature is 90xc2x0 C. has been described by Sankaran and Reynolds, polym. Mater. SCI 72, 1995, 319-320.
There is therefore a need for a process for the alkylation of 3,4-dihydroxythiophene-2,5-dicarboxylic esters or their alkali metal or alkaline earth metal salts which is simple to carry out and gives good yields of the corresponding 3,4-dialkoxythiophene-2,5-dicarboxylic esters and 3,4-alkylenedioxythiophene-2,5-dicarboxylic esters at comparatively short reaction times.
We have now surprisingly found a process for the alkylation of compounds of the formula (I) 
where
R1 and R2 are identical and are each hydrogen or are identical or different and are each an alkali metal or an alkaline earth metal and
R3 and R4 are identical or different and are each a straight-chain or branched alkyl radical having from 1 to 10 carbon atoms,
comprising reacting said compounds with alkylating agents in a polar diluent, wherein the reaction is carried out in the presence of quaternary onium salts of the formula (II) 
where
A is nitrogen or phosphorus,
Yxe2x88x92 is an anion and
R5 to R8 are identical or different and are each an alkyl radical having from 1 to 20 carbon atoms, an aryl radical having from 6 to 15 carbon atoms or an aralkyl radical having from 7 to 20 carbon atoms.
The process of the invention allows the alkylation of compounds of the formula (I) under mild conditions at low temperatures and short reaction times while giving excellent yields.
In the process of the invention, preference is given to using compounds of the formula (I) in which R1 and R2 are identical or different and are each an alkali metal or an alkaline earth metal, for example lithium, sodium, potassium, rubidium, magnesium, calcium or strontium. They are obtained from the corresponding free 3,4-dihydroxythiophene-2,5-dicarboxylic esters by addition of alkali metal alkoxide or carbonate or alkaline earth metal alkoxide or carbonate or are obtained directly in the preparation of 3,4-dihydroxythiophene-2,5-dicarboxylic esters by reaction of thiodiacetic esters with oxalic esters in the presence of alkali metal alkoxide (xe2x80x9cHinsberg condensationxe2x80x9d). Particular preference is given to using compounds of the formula (I) in which R1 and R2 are identical or different and are each an alkali metal, for example lithium, sodium, potassium or rubidium.
If compounds of the formula (I) in which R1 and R2 are different are used, then R1 is particularly preferably sodium and R2 is particularly preferably potassium.
Very particular preference is given to using compounds of the formula (I) in which R1 and R2 are identical and are each lithium, sodium, potassium or rubidium, among which sodium and potassium are preferred.
The process of the invention is preferably carried out using compounds of the formula (I) in which R3 and R4 are identical or different and are each a straight-chain or branched alkyl radical having from 1 to 8 carbon atoms, particularly preferably a straight-chain or branched alkyl radical having from 1 to 6 carbon atoms, for example methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, n-pentyl, branched pentyls, n-hexyl, branched hexyls, 2-methylbutyl or 2-ethylbutyl.
If compounds of the formula (I) in which R3 and R4 are identical are used in the process of the invention, then R3 and R4 are each preferably methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, 2-methylbutyl or 2-ethylbutyl, particularly preferably methyl, ethyl, n-propyl or isopropyl, with the compounds mentioned being particularly preferably used in the form of their disodium or dipotassium salts (R1 and R2 are identical and are each sodium or potassium), very particularly preferably in the form of their disodium salt (R1 and R2 are identical and are each sodium). Very particular preference is given to using dimethyl 3,4-dihydroxythiophene-2,5-dicarboxylate in the form of its disodium salt.
In a preferred embodiment of the process of the invention, use is made of mixtures of compounds of the formula (I) as are obtained, for example, in the preparation of 3,4-dihydroxythiophene-2,5-dicarboxylic esters by reacting dibutyl thiodiacetate with diethyl oxalate in the presence of sodium methoxide in methanol (xe2x80x9cHinsberg condensationxe2x80x9d). These are preferably mixtures in which R3 and R4 are identical or different and are each methyl, ethyl or butyl. Particular preference is given to using mixtures comprising dimethyl 3,4-dihydroxythiophene-2,5-dicarboxylate, methyl ethyl 3,4-dihydroxythiophene-2,5-dicarboxylate and methyl butyl 3,4-dihydroxythiophene-2,5-dicarboxylate. Very particular preference is given to using mixtures in the form of their salts (R1 and R2 are identical or different and are each an alkali metal or an alkaline earth metal), in which case particular preference is given to R1 and R2 being identical and each being sodium or potassium and very particular preference is given to R1 and R2 being identical and each being sodium. In a very particularly preferred embodiment, a mixture comprising the disodium salt of dimethyl 3,4-dihydroxythiophene-2,5-dicarboxylate, the disodium salt of methyl ethyl 3,4-dihydroxythiophene-2,5-dicarboxylate and the disodium salt of methyl butyl 3,4-dihydroxythiophene-2,5-dicarboxylate is used in the process of the invention.
The alkylating agents used in the process of the invention are customary alkylating agents known to those skilled in the art.
It is possible to use alkylating agents which contain only one leaving group and on reaction with the compounds of the formula (I) used in the process of the invention lead to compounds of the formula (III) 
where
R9 and R10 are straight-chain or branched alkyl radicals which originate from the alkylating agent used in the particular case and
R3 and R4 are as defined above.
Preference is here given to alkylating agents selected from the group consisting of alkyl halides, alkyl sulphates, alkyl methanesulphonates, alkyl benzene sulphonates and alkyl toluene sulphonates, preferably straight-chain or branched C1-C8-alkyl halides, sulphates, methane sulphonates, benzene sulphonates and toluene sulphonates. Particular preference is given to using alkyl halides, preferably straight-chain or branched C1-C8-alkyl halides, very particularly preferably straight-chain or branched C1-C8-alkyl chlorides or bromides, in particular dimethyl sulphate, methyl chloride, methyl bromide or methyl iodide.
Preference is given to using alkylating agents which contain two leaving groups and on reaction with the compounds of the formula (I) used in the process of the invention lead to compounds of the formula (IV) 
where
R11 is a straight-chain or branched alkylene radical which originates from the alkylating agent used in the particular case and
R3 and R4 are as defined above.
Preference is here given to using alkylating agents selected from the group consisting of alkyl dihalides, alkyl disulphates, alkyl dimethane sulphonates, alkyl dibenzene sulphonates and alkyl ditoluene sulphonates, preferably straight-chain or branched C1-C8-alkyl dihalides, disulphates, dimethane sulphonates, dibenzene sulphonates and ditoluene sulphonates. Particular preference is given to using alkyl dihalides, preferably straight-chain or branched C1-C8-alkyl dihalides, very particularly preferably straight-chain or branched C1-C8-alkyl dichlorides or dibromides, in particular 1,2-bis(mesyloxy)ethane, 1,2-dichloroethane, 1,2-dibromoethane and 1-bromo-2-chloroethane, among which very particular preference is given to 1,2-dichloroethane.
The alkylating agent used in the process of the invention is used in at least the stoichiometric amount; in general, it is advantageous to use an excess. Preference is given to using an excess of from 30 to 200 mol %, particularly preferably an excess of from 50 to 150 mol %, in particular an excess of from 70 to 100 mol %, based on the compounds of the formula (I).
The polar diluents used in the process of the invention are customary polar diluents known to those skilled in the art. They can be used alone or in the form of mixtures. It is also possible to use polar diluents in the form of mixtures with nonpolar diluents.
Polar diluents used are preferably aprotic polar diluents selected from the group consisting of ethers, ketones, esters, amides, ureas, sulphoxides and sulphones, particularly preferably diethylene glycol dimethyl ether, dioxane, acetone, cyclohexanone, butyl acetate, N,N-dimethylformamide N-methylpyrrolidone, hexamethylphosphoramide, tetramethyl urea, dimethyl sulphoxide or tetramethylene sulphone (sulpholane).
The process of the invention is preferably carried out using quaternary onium salts of the formula (II) in which Y31  is an anion selected from the group consisting of chloride, bromide, iodide, hydroxide, hydrogen sulphate, sulphate, methane sulphonate, toluene sulphonate and trifluoroacetate, particularly preferably chloride or bromide.
The process of the invention is preferably carried out using quaternary onium salts of the formula (II) in which R5 to R8 are identical or different and are each an alkyl radical having from 1 to 16 carbon atoms, an aryl radical having from 6 to 10 carbon atoms, for example phenyl or naphthyl, or an aralkyl radical having from 7 to 11 carbon atoms, for example benzyl, phenylmethyl or phenylethyl, particularly preferably methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, decyl, dodecyl, tetradecyl, phenyl or benzyl.
The process of the invention is particularly preferably carried out using quaternary onium salts of the formula (II) in which R5 to R8 are identical and are each an alkyl radical having from 1 to 6 carbon atoms, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, n-pentyl, branched pentyls, n-hexyl or branched hexyls, particularly preferably methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl or tert-butyl.
Very particular preference is given to using quaternary onium salts of the formula (II) selected from the group consisting of tetramethylammonium chloride, tetramethylammonium bromide, benzyldimethyltetradecyl-ammonium chloride, butyltriphenylphosphonium bromide, tetraphenylphosphonium bromide and tetrabutylphosphonium chloride in the process of the invention.
The quaternary onium salts of the formula (II) used in the process of the invention can be used individually or in the form of mixtures of various onium salts. Furthermore, they can be used as such or in the form of precursor compounds which are converted in situ into onium salts of the formula (II) under the conditions of the process of the invention, for example, tertiary amines or phosphines which are alkylated under the reaction conditions to form quaternary ammonium salts or phosphonium salts.
The onium salts used in the process of the invention are preferably used in a substoichiometric amount, preferably in an amount of from 1 to 20 mol %, based on dihydroxythiophene derivative (starting material), particularly preferably from 2 to 10 mol %, very particularly preferably in an amount of from 3 to 7 mol %, based on dihydroxythiophene derivative (starting material).
In a preferred embodiment, the process of the invention is carried out in the presence of an additional base, particularly preferably in the presence of alkali metal or alkaline earth metal carbonates, hydroxides, oxides or alkoxides, very particularly preferably in the presence of alkali metal carbonates, in particular sodium carbonate or potassium carbonate.
If an additional base is employed, it is preferably used in a substoichiometric to equivalent amount, preferably an amount of from 5 to 100 mol %, particularly preferably from 10 to 80 mol %, very particularly preferably from 25 to 50 mol %, based on the compounds of the formula (I).
The process of the invention is preferably carried out at a temperature of from 50 to 150xc2x0 C. If 1,2-dichloroethane or 1,2-dibromoethane is used as alkylating agent, the process is preferably carried out at a temperature of from 100 to 140xc2x0 C.
The process of the present invention is preferably carried out at atmospheric pressure or under superatmospheric pressure, preferably from 1 to 30 bar. Working under superatmospheric pressure permits the use of diluents whose boiling point at atmospheric pressure is significantly above the desired process temperature.
The process of the invention is preferably carried out by placing the diluent in a reaction vessel and adding preferably firstly compounds of the formula (I), quaternary onium salts of the formula (II) and preferably a base. The mixture is preferably brought to the desired reaction temperature and the alkylating agent is subsequently added, preferably dropwise. After the reaction is complete, compounds of the formula (III) or (IV) are obtained as products. These can be isolated and purified by pouring into water, filtration and recrystallization. In a preferred embodiment, these compounds are not isolated and purified. The compounds of the formula (III) or (IV) are, preferably after removal of at least part of the diluent, for example by distillation, hydrolysed to the corresponding carboxylic acids by methods known from the literature. These acids can, for example, be isolated by filtration or centrifugation after acidification of the reaction mixture.
In a particularly preferred embodiment of the process of the invention, 3,4-dihydroxy-2,5-thiophenedicarboxylic esters in the form of their salts, either individually or in the form of a mixture of various esters, are reacted with 1,2-dichloroethane and the resulting ester is hydrolysed to give 3,4-ethylenedioxythiophene-2,5-dicarboxylic acid in the form of a hitherto unknown, new monohydrate. Hitherto, 3,4-ethylenedioxythiophene-2,5-dicarboxylic acid has always been used as anhydrous compound obtained from the dihydrate by a separate drying step. However, the anhydrous compound is not stable on storage since it gradually attracts atmospheric moisture. The use of the new storage-stable monohydrate therefore has economic advantages.
The invention is further illustrated but is not intended to be limited by the following examples in which all parts and percentages are by weight unless otherwise specified.